Pancreatic islet transplantation is less efficient than whole organ pancreas transplantation in reversing the hyperglycemia of diabetes. One of the major reasons for this disparity is the loss of islets to ischemic injury during the time it takes for the islets to revascularize in the recipient. We have recently developed techniques for constructing composite "islet kidneys" (IK) by transplantation of autologous islets under the kidney capsule 2-3 months prior to transplantation of the composite organ into pancreatectomized miniature swine. Transplantation of IKs was found to restore euglycemia to pancreatectomized recipients immediately, and to maintain both renal and islet function long-term. Our preliminary data indicate further that a single living donor pancreas contains sufficient islets to support the insulin requirements of both the donor and recipient of such a prevascularized IK. The goal of this combined R21/R33 proposal is to perfect and optimize this approach in preclinical models (R21) and then to extend the procedure to the treatment of diabetic patients with end-stage renal disease. Specifically, in phase I (R21) we will: 1) Determine the optimal donor pancreatectomy requirements for clinical applicability; 2) Compare the efficacy of IK in maintaining euglycemia following tolerance induction vs. standard maintenance immunosuppression; 3) Establish an IK transplantation model in baboons and assess the ability of allogeneic IK transplantation to reverse hyperglycemia in diabetic baboons. In phase II (R33) we will: 1) Develop laparoscopic techniques for partial pancreatectomy, preparation of IK and IK removal for transplantation; and 2) Extend IK technology to the treatment of a major subset of patients with type 1 diabetes whose disease has progressed to end-stage renal failure. The research team assembled for this "bench-to-bedside" approach includes: 1) basic scientists in the Transplantation Biology Research Center, who have been responsible for the preliminary data on which the application is based, 2) clinicians at the Massachusetts General Hospital involved in transplantation and diabetes research, and 3) consultants with outstanding expertise related to the techniques to be developed. We anticipate that the use of pre-vascularized islets as part of a composite islet-kidney transplant may provide a new and effective treatment modality for patients with class I diabetes and end-stage renal disease.